What are the diagnostic criteria for familial hyperlipidemia?

Diagnostic Criteria for Familial Hypercholesterolemia

The diagnosis of familial hypercholesterolemia (FH) should be made using validated clinical criteria such as the Dutch Lipid Clinic Network or Simon Broome criteria, with genetic testing as the gold standard when available. 1, 2

Clinical Diagnostic Criteria

Dutch Lipid Clinic Network Criteria

This is one of the most widely used diagnostic tools for FH, which assigns points based on:

• LDL-C levels:

  • 8.5 mmol/L (>330 mg/dL): 8 points

  • 6.5-8.4 mmol/L (250-329 mg/dL): 5 points
  • 5.0-6.4 mmol/L (190-249 mg/dL): 3 points
  • 4.0-4.9 mmol/L (155-189 mg/dL): 1 point

• Physical findings:

  • Tendon xanthomas: 6 points
  • Arcus cornealis before age 45: 4 points

• Family history:

  • First-degree relative with premature cardiovascular disease: 1 point
  • First-degree relative with LDL-C >95th percentile: 1 point
  • First-degree relative with tendon xanthomas and/or arcus cornealis: 2 points
  • Children <18 years with LDL-C >95th percentile: 2 points

• Personal history:

  • Premature coronary artery disease: 2 points
  • Premature cerebral/peripheral vascular disease: 1 point

• Genetic testing:

  • Functional mutation in LDLR, APOB, or PCSK9 genes: 8 points

Diagnosis based on total score:

• Definite FH: >8 points
• Probable FH: 6-8 points
• Possible FH: 3-5 points
• Unlikely FH: <3 points

Simon Broome Criteria

Alternative diagnostic criteria that classify FH as "definite" or "possible" based on:

• Definite FH:

  • Elevated cholesterol (total >7.5 mmol/L or LDL >4.9 mmol/L in adults; total >6.7 mmol/L or LDL >4.0 mmol/L in children under 16)
  • PLUS either tendon xanthomas in patient or first/second-degree relative
  • OR genetic evidence of mutation in LDLR, APOB, or PCSK9

• Possible FH:

  • Elevated cholesterol as above
  • PLUS family history of myocardial infarction before age 50 in second-degree relative or before age 60 in first-degree relative
  • OR family history of elevated cholesterol in first or second-degree relative

Genetic Testing

Genetic testing is the gold standard for diagnosis of FH and should be offered to all index patients with a phenotypic diagnosis of FH, especially if cascade testing is planned 1, 2. The most common genetic causes are:

• Mutations in LDLR gene (most common)
• Mutations in APOB gene
• Mutations in PCSK9 gene
• Mutations in LDLRAP1 gene (rare, autosomal recessive)

A negative genetic test does not rule out FH if the clinical presentation strongly suggests the condition, as current genetic testing identifies mutations in only about 80% of clinically diagnosed cases 3.

Diagnostic Approach for Different Populations

Adults

1. Measure fasting or non-fasting lipid profile
2. Apply clinical criteria (Dutch Lipid Clinic Network or Simon Broome)
3. Consider genetic testing for confirmation, especially if:
   • LDL-C >4.9 mmol/L (>190 mg/dL)
   • Family history of premature cardiovascular disease
   • Physical findings suggestive of FH

Children

1. Screening recommended from age 5 years (or as early as 2 years with strong family history) 2
2. Diagnosis relies on:
   • Elevated LDL-C (>3.5 mmol/L or >135 mg/dL)
   • Positive family history of premature coronary artery disease
   • High LDL-C in at least one parent 1
3. In children, an LDL-C level ≥3.5 mmol/L (≥135 mg/dL) has been shown to predict FH with a 0.98 posttest probability 1

Homozygous FH (HoFH)

• Characterized by markedly elevated LDL-C levels, typically >13 mmol/L (>500 mg/dL)
• Can occur with LDL-C <10 mmol/L (<400 mg/dL) 1, 2
• Usually presents with severe xanthomas and cardiovascular disease in childhood
• Genetic testing showing biallelic pathogenic variants confirms diagnosis

Important Clinical Considerations

1. Adjust for lipid-lowering therapy: When patients are already on treatment, untreated LDL-C levels should be estimated by multiplying the on-treatment value by a correction factor based on the specific medication and dose 1.

2. Consider Lp(a) levels: High lipoprotein(a) concentrations may affect the phenotypic diagnosis of FH and should be considered when evaluating borderline cases 1.

3. Cascade screening: Once an index case is identified, all first-degree relatives should be screened using both phenotypic criteria and genetic testing when available 2.

4. Avoid diagnosis during acute illness: Lipid measurements should be performed when patients are not acutely ill, as acute illness can affect lipid levels 1.

5. Pediatric diagnosis: Should ideally be made by a pediatrician with training in lipidology, with attention to psychological impact on the family 1.

Early diagnosis is crucial as the atherosclerotic burden depends on both the degree and duration of exposure to elevated LDL-C levels 2, 4. With proper diagnosis and treatment, the risk of premature cardiovascular disease can be significantly reduced.